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Murine Allogeneic CAR-T Cells Integrated Before or Early After Posttransplant Cyclophosphamide Exert Anti-Tumor Effects

ABSTRACT: The direct integration of chimeric-antigen-receptor (CAR) T cell with allogeneic hematopoietic cell transplantation (allo-HCT) carries the risk of graft-versus-host disease (GVHD) induction by allogeneic CAR-T cells. Based on our past experiments, it has been shown that post-transplantation cyclophosphamide (PTCy) prevents GVHD induction by other cell infusions after T-cell-replete MHC-haploidentical murine allo-HCT models. In this study, we investigated whether CAR-T cells, given in a similar manner in the same MHC-haploidentical murine allo-HCT model, could safely exert anti-tumor effects. We showed that anti-CD19 CAR-T cells administered early after (day +5 of transplant) or prior to (day 0 of transplant) PTCy for allo-HCT cleared leukemia without toxicity or GVHD exacerbation. Using next generation single-cell RNA sequencing approaches, we demonstrated that in comparison to CAR-T cells infused early after PTCy (day +5), CAR-T cells infused prior to PTCy (day 0) exhibited transcriptional changes consistent with increased CD4+ T-cell activation and CD8+ T-cell cytotoxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE214788 | GEO | 2022/10/09

REPOSITORIES: GEO

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Evolutionarily conserved effects of Notch signaling drive intestinal graft-versus-host disease in mice and non-human primates

Project description:Notch signaling promotes T-cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like ligand DLL4. To assess if Notch’s effects are evolutionarily conserved and identify key mechanisms, we studied antibody-mediated DLL4 blockade in a non-human primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved post-transplant survival with striking, durable protection from gastrointestinal GVHD, out of proportion to other disease sites. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T-cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4β7 in conventional T-cells while preserving α4β7 in regulatory T-cells, with findings suggesting increased 1 competition for 4 binding in conventional T-cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4β7 integrin in T-cells after allo-HCT. Altogether, DLL4/Notch blockade decreased effector T-cell infiltration into the gut, with increased regulatory to conventional T-cell ratios early after allo-HCT. Our results identify a conserved, biologically unique and targetable role of DLL4/Notch signaling in GVHD.

2023-07-14 | GSE228838 | GEO

Expression Profile of alloreactive CD8 and CD4 induced regulatory T cells

Project description:Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versus-leukemic (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4 or CD8 T cells and tested their ability to suppress GVH and maintain GVL responses. We utilized major mismatched and haploidentical murine models of HCT with host-derived lymphoma or leukemia cell lines to evaluate GVH and GVL responses simultaneously. Alloreactive CD4 iTregs were effective in preventing GVHD, but abrogated the GVL effect against aggressive leukemia. Alloreactive CD8 iTregs moderately attenuated GVHD while sparing the GVL effect. Hence, we reasoned that using a combination of CD4 and CD8 iTregs could achieve the optimal goal of allo-HCT. Indeed, the combinational therapy was superior to CD4 or CD8 iTreg singular therapy in GVHD control; importantly, the combinational therapy maintained GVL responses. Cellular analysis uncovered potent suppression of both CD4 and CD8 effector T cells by the combinational therapy that resulted in effective prevention of GVHD, which could not be achieved by either singular therapy. Gene expression profiles revealed alloreactive CD8 iTregs possess elevated expression of multiple cytolytic molecules compared to CD4 iTregs, which likely contributes to GVL preservation. Our study uncovers unique differences between alloreactive CD4 and CD8 iTregs that can be harnessed to create an optimal iTreg therapy for GVHD prevention with maintained GVL responses.

2016-11-17 | GSE75118 | GEO

Effect of hBD-2 treatment on gene expression in the colon of acute graft-versus-host disease (GVHD) mice

Project description:Wildtype (WT) BALB/c mice were treated with allogeneic hematopoietic cell transplantation (allo-HCT) in order to induce acute GVHD. C57BL/6 mice were used bone marrow (BM) and T cell donor mice. We studied the effect of oral hBD-2 treatment versus vehicle (PBS) control treatment on the gene expression in the colon, as main GVHD target organ.

2022-12-23 | GSE190796 | GEO

Immune Mediated Disorders after Allo-HCG

Project description:Allogeneic hematopoietic cell transplantation (HCT) is the only known curative option for many hematologic disorders. After transplantation, many patients develop immune mediated disorders that may be life-threatening. Post-HCT immune mediated disorders are rare relative to other diseases but the prototype of graft versus host disease (GVHD) develops in 30-70% of patients. The morbidity and mortality associated with these HCT-associated immune mediated disorders are major barriers to successful use of transplantation to cure rare hematologic malignancies such as leukemia, lymphoma, multiple myeloma, myelodysplastic/myeloproliferative syndromes amongst other diseases. The purpose of this study is to characterize and more completely define the onset and course of immune mediated disorders after allogeneic HCT, focusing on participants who develop cutaneous sclerosis, bronchiolitis obliterans syndrome (BOS), late acute graft-vs.-host disease (GVHD), and chronic GVHD. <ul> <li>Of the participants undergoing allogeneic hematopoietic cell transplantation (HCT), can we, the researchers better identify who will develop immune-mediated disorders, what types of disorders participants will have, and whether these disorders will be severe or respond to currently available therapies?</li> </ul> This is a longitudinal study of 1118 individuals (1081 adults and 100 children). Those participating in this study will be evaluated over a 3 year period at 9 study sites. Participants will be enrolled pre-transplant, or up to day 121 post transplantation. This wide enrollment window will allow sites to use recruitment methods that are most efficient at their institutions. At least 2 years of follow-up will ensure an adequate sample size, and sufficient time for observation of the full spectrum of immune mediated disorders. The data of 1023 individuals have been submitted to dbGaP.

| phs001331 | dbGaP

Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [17941R-18740R]

Project description:Lymphocyte subsets (CD8, CD4 Tconv, NK cells) were sorted from patients' peripheral blood obtained on day 28 after haploidentical-donor allogeneic bone marrow transplantation followed by posttransplant cyclophosphamide (PTCy), tacrolimus, and MMF as GVHD prophylaxis (NCT00796562). Cohort of patients developed GVHD, or remained GVHD-free. Cohort of patients developed disease relapse, or remained relapse-free. RNA-sequencing was performed to analyze the transcriptional landscape of alloresponse in post-PTCy breakthrough GVHD and relapse.

2021-09-28 | GSE182612 | GEO

Single-cell RNA sequencing analysis of blood B cells from human allogeneic hematopoietic transplant patients

Project description:Single cell analysis of gene expression in blood B cells from allogeneic hematopoietic stem cell transpant (HCT) patients that either developed chronic GVHD, or never developed chronic GVHD.

2023-05-02 | GSE161343 | GEO

Faecal Microbiota Transplantation After Allogeneic Stem Cell Transplantation

Project description:The aim of this study is to assess the Fecal Microbiota Transplantation (FMT) efficacy in the prevention of allogeneic hematopoietic stem cell transplantation (allo-HSCT) complications and particularly Graft versus Host Disease (GvHD). The hypothesis of this study is that allogeneic FMT may improve outcomes of these patients.

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Expansion, persistence and efficacy of donor memory-like NK cells for the treatment of post-transplant relapse

Project description:Relapse of AML occurs in up to 50% of patients after allogeneic hematopoietic stem cell transplant (HCT) and heralds an extremely poor prognosis. Cytokine induced memory-like (CIML) human NK cells have enhanced ability to recognize and kill leukemia targets. We initiated a phase I trial of CIML NK cells to treat patients with relapsed myeloid malignancies after haplo-HCT (NCT04024761). Transcriptional profiling analysis by scRNAseq were used to characterize the immunophenotypes of infused NK cells post cell adoptive transfer and as well as their interactions with tumor cells.

2022-03-11 | GSE198141 | GEO

Immune Escape after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with Acute Myeloid Leukemia

Project description:Although allogeneic hematopoietic cell transplantation (allo-HCT) is curative for high-risk pediatric acute myeloid leukemia (AML), disease relapse remains the primary cause of post-transplant mortality. To identify pressures imposed by allo-HCT on AML cells that escape the graft-versus-leukemia effect, we evaluated immune signatures in bone marrow samples from four pediatric patients using a multimodal single-cell approach. Downregulation of MHC class II (MHC-II) expression observed at post-transplant relapse was most profound in progenitor-like blasts and was accompanied by correlative changes in transcriptional regulation. Dysfunction of activated NK cells and CD8+ T cell subsets at the time of relapse was evidenced by the loss of IFN-γ response, TNF-a signaling via NF-kB, and IL-2/STAT5 signaling. Clonotype analysis of post-transplant relapse samples revealed expansion of dysfunctional T cells and enrichment of T regulatory and T helper cells. Using novel computational methods, our results illustrate a diverse immune-related transcriptional signature in post-transplantation relapses not previously reported in pediatric AML.

2023-06-26 | GSE207104 | GEO

Allogeneic antibodies specifically target AML antigen NuSAP1 after bone marrow transplantation

Project description:Identifying the targets of immune response after allogeneic hematopoietic cell transplantation (HCT) promises to provide relevant immune therapy candidate proteins. We used protein microarrays to serologically identify Nucleolar and Spindle Associated Protein 1 (NuSAP1) and Chromatin Assembly Factor 1, subunit B (p60) [CHAF1b] as targets of new antibody responses that developed after allogeneic HCT. Western blots and ELISA validated their post-HCT recognition and enabled ELISA testing of 120 other allo-HCT patients. CHAF1b specific antibodies were predominantly detected in AML patients whereas NuSAP1 specific antibodies were exclusively detected in AML patients one year post-transplant (p<0.0001). Complete genomic exon sequencing failed to identify a nonsynonymous SNP for NuSAP1 and CHAF1b between the donor and recipient cells. Expression profiles and RT-PCR showed NuSAP1 was predominately expressed in the bone marrow CD34+CD90+ hematopoietic stem cells (HSC), leukemic cell lines and B lymphoblasts as compared to other tissues or cells. Thus, NuSAP1 is recognized as an immunogenic antigen in 65% AML patients and suggests a tumor antigen role. In conclusion, clinically important tumor antigens can be identified as new antibody targets after allogeneic HCT using high density protein microarrays

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